Papilloma viruses are non-enveloped DNA viruses with a double stranded circular genome of approximately 8,000 bp. Over 75 types of human papilloma viruses (HPV) have been typed at the DNA level, and these can be broadly grouped into families on the basis of their tissue tropism.
Histologic, molecular, and epidemiologic evidence have implicated some HPV strains in cervical dysplasia and cervical cancer. Many studies support the view that most moderate and severe cervical intraepithelial neoplasias (CIN) contain HPV DNA which is exclusively detected in the histologically abnormal epithelium of these lesions. Persistent infection with HPV is believed to be the predominant risk factor for development of cervical carcinoma. HPV DNA is readily found in episomal form within cells exhibiting a cytopathic effect, while the HPV DNA is found integrated within the chromosomes of cells associated with most high grade pre-cancerous lesions and cancer. Approximately 23 HPV types are commonly found in anogenital screening programs, but only 10–15 are associated with progressive disease. Type 16 is the type most commonly found in cervical cancer tissue.
Papillomaviruses contain nine open reading frames. HPV genes with transforming properties have been mapped to open reading frames E6 and E7. Substantial biochemical work has demonstrated that the HPV E6 protein inactivates the protein p53, whereas the E7 protein interferes with retinoblastoma (Rb) protein function. Since p53 and Rb are tumor-suppressor proteins which function as cell division inhibitors, their inactivation by E6 and E7 leads the cell to enter into S phase of the cell cycle. Expression of E6 and E7 is sufficient to immortalize some primary cell lines, and blocking E6 or E7 function has been shown to reverse the transformed state.
Abundant circumstantial evidence implicates host immune mechanisms in the control of HPV associated tumours of the anogenital epithelium (Singer et al., British Medical Journal 288: 735–736, 1984). There is an increased incidence of pre-neoplastic (Frazer et al., Lancet ii 657–660, 1986) and neoplastic associated lesions in homosexual men immunosuppressed by human immunodeficiency virus infection and a markedly increased risk of squamous cell carcinoma (SCC) of the cervix and vulva but not of control organs such as breast and rectum in immunosuppressed allograft recipients (Sheil and Plavel Ninth Report of Australian and New Zealand Combined Dialysis and Transplant Registry pp 104–112 Edited by APS Disney 1986).
Taken with the above, the normal natural history of HPV infection in most patients with alpha-gamma globulinemia suggests that cellular rather than humoral responses are important for the control of the phenotypic expression of HPV infection (Kirschner Progress in Medical Virology, 1986).
Standard immunological approaches to the study of anogenital HPV infection have been hampered by the lack of a suitable animal model and of an in vitro epithelial cell culture permissive for HPV. Vaccines have also been proposed in regard to HPV with however only indifferent success.
It has been proposed to use vaccines containing autogenous tumor homogenates (Abcarian et al., J. Surg Res 22: 231–236, 1977, Dis. Colon Rectum 25:648–51, 1982, Dis. Colon Rectunt 19: 237–244, 1976. However it has recently been advocated that patients should no longer be treated with autogenous vaccines because of the potential oncogenic effect of the viral DNA (Bunney Br Med. J 293:1045–1047, 1986).
Data on successful prophylactic vaccination exist only for bovine fibropapillomas homogenized homogenate of bovine fibropapillomas and has been shown to provide limited immunity (Olson et al., J Am Vet Med. Assoc. 135: 499, 1959, Cancer Res 22: 463, 1962). A vaccine including an engineered L1 fusion protein (Pilacinski et al., UCLA Symp. Molecular and Cellular Biology New Series Vol 32 Papilloma Viruses Molecular and Clinical Aspects Alan R Liss New York, pg. 257,1985) has also been used in calves but proved unsuccessful in humans. In Pfister, PAPILLOMA VIRUSES AND HUMAN CANCER, CRC Press Inc. (1990) it is stated that there is presently no evidence for a possible prevention of HPV infection by the use of a capsid protein vaccine, but induction of an anti-tumor cell immunity appears to be feasible.
The L1 and L2 genes have been the basis of vaccines for the prevention and treatment of papilloma virus infections and immunogens used in the diagnosis and detection of papilloma viruses (International Patent Specifications W0 86/05816 and E 08303623). However, it appears that no commercial usage of these vaccines have taken place.
Reference may also be made to Patent Specification EP 386734 which describes new immunogenic regions of HPV-16 E7 protein which may be useful in vaccines, EP 375555 which describes HPV-16 peptides useful as immunoassay reagents for the detection of HPV-16 proteins and which contain an antigenic determinant for HPV16, a reference in VACCINE 83: 199–204 (1990) which describes vaccines including recombinants expressing HPV E5, E6 or E7 ORF intended for use in providing antitumor activity, Australian Specification 52860/90 which describes screening antibodies for specificity to an antigen which is an epitope of HPV-16 L1 or E7 proteins, Australian Specification 75535/87 which describes synthetic peptides of HPV corresponding to an amino acid sequence region having at least one reverse turn and predicted hydrophilicity, Patent Specification EP 217919 which describes type specific papillomavirus DNA sequences and peptides useful in vaccines containing 15–75 nucleotides, U.S. Pat. No. 4,551,270 which describes at least one antigenic determinant of papillomavirus and immunogens and vaccines containing the antigenic determinant, Patent Specification EP 412762 which describes a polypeptide, which inhibits binding of the HPV E7 protein to retinoblastoma gene which may be used in vaccines for treatment of cervical cancer and genital warts, French Specification 2643817 which describes a vaccine for treatment of tumours induced by papillomavirus containing recombinant poxvirus with heterologous DNA encoding region of non structural papillomavirus, Japanese Specification J01061665 which describes antibodies formed to an antigen polypeptide of HPV-16E6 or E7 protein, Australian Specification 76018/87 which describes expression products of HPV-16 or HPV-18 which may be used for the production of antibodies, EP235187 which describes kits containing polypeptide(s) expressed by several groups of papilloma virus including HPV-16 and HPV-18 which are expression products of E6, E7 or L2 genes and U.S. Pat. No. 4,777,239 which includes, diagnostic synthetic peptides for HPV one of which includes residues 45–58 of protein E6 and 40–50 of protein E7 which may be used as a therapeutic agent.
Virus-specific, human leukocyte antigen (HLA) class I-restricted cytotoxic T lymphocytes (CTL) are known to play a major role in the prevention and clearance of virus infections in vivo (Oldstone et al, Nature 321:239, 1989; Jamieson et al., J. Virol. 61:3930, 1987; Yap et al, Nature 273:238, 1978; Lukacher et al., J. Exp. Med. 160:814, 1994; McMichael et al., N. Engl. J. Med. 309:13, 1983; Sethi et al., J. Gen. Virol. 64:443, 1983; Watari et al., J. Exp. Med. 165:459, 1987; Yasukawa et al, J. Immunol. 143:2051, 1989; Tigges et al., J. Virol. 66:1622, 1993; Reddenhase et al. J. Virol. 55:263, 1985; Quinnan et al., N. Engl. J. Med. 307:6, 1982). HLA class I molecules are expressed on the surface of almost all nucleated cells. Following intracellular processing of antigens, epitopes from the antigens are presented as a complex with the HLA class I molecules on the surface of such cells. CTL recognize the peptide-HLA class I complex, which then results in the destruction of the cell bearing the HLA-peptide complex directly by the CTL and/or via the activation of non-destructive mechanisms e.g., the production of interferon, that inhibit viral replication.